Influence of loperamide and loperamide oxide on the anal sphincter

The objective of this study was to investigate the effects of the opioid loperamide and its recently synthesized pharmacologically inactive prodrug loperamide oxide on the anal sphincter. In a double-blind, placebo-controlled crossover study, anorectal manometry was performed in 12 healthy volunteers five hours after oral bolus application of 10 mg of loperamide, loperamide oxide, or placebo. Loperamide significantly increased the threshold volumes for minimal perception and urgency to defecate (P <0.05) and raised the volume required to abolish recovery of the rectoanal inhibitory reflex (P < 0.05). These findings suggest that loperamide has a specific continence-improving action on the anal sphincter. However, anal resting pressure and maximal squeeze pressure were unaffected in our study and do not seem to be responsible for this effect. The effects under loperamide oxide showed a similar tendency but were without statistical significance.     

Effects of galanin on the opossum internal anal sphincter: structure-activity relationship.

The present study was carried out to investigate the effects of porcine galanin-(1-29), N-terminal fragment galanin-(1-10), C-terminal fragment galanin-(15-29), and the middle fragment galanin-(7-16) on the spontaneous tension of the opossum internal anal sphincter and on the decrease in the resting internal anal sphincter tension in response to neural stimulation by electrical field stimulation. Galanin and galanin-(1-10) caused a concentration-dependent decrease in the resting tension of internal anal sphincter and an augmentation of the percent decrease in the resting tension with electrical field stimulation. Galanin-(15-29), on the other hand, produced an increase in the resting tension of the internal anal sphincter and had no effect on the electrical field stimulation-induced decrease in the resting tension. Galanin-(7-16) produced no significant effect on the internal anal sphincter. The decrease in the internal anal sphincter tension by galanin and galanin-(1-10) was partially antagonized by tetrodotoxin, whereas the increase in the internal anal sphincter tension caused by galanin-(15-29) was not modified by tetrodotoxin. In contrast to its effect in the internal anal sphincter, galanin caused an increase in the resting tension and suppressed a decrease in the lower esophageal sphincter tension in response to electrical field stimulation. From these findings we conclude that (a) galanin exerts an inhibitory effect on the internal anal sphincter by activating galanin receptors both at the intramural inhibitory neurons and at the internal anal sphincter smooth muscle and that the N-terminal portion of galanin may be responsible for these actions; (b) the contractile action of galanin is produced by its action on the smooth muscle; and (c) the actions of galanin on the gastrointestinal tract are tissue specific.     

Nitric oxide pathway in rectoanal inhibitory reflex of opossum internal anal sphincter.

The role of nitric oxide in relaxation of the internal anal sphincter (IAS) in response to the rectoanal reflex was studied in the opossum. Resting pressures in the IAS (IASP) were monitored using low-compliance continuously perfused catheters. The NO-synthase inhibitor L-NG-nitro-arginine (L-NNA) caused significant and dose-dependent suppression of the decrease in IASP in response to the reflex mimicked by the rectal balloon distention. NO-synthase inhibitor blocked IAS relaxation in response not only to rectoanal reflex but also to other neural stimuli such as sacral nerve stimulation, local intramural stimulation, and the nicotinic ganglionic stimulant 1,1-dimethyl-4-phenylpiperazinium. Suppression of the neurally mediated IAS relaxation by L-NNA was stereoselective; D-NNA had no effect on the relaxation. The suppression of the rectoanal reflex-induced IAS relaxation by L-NNA was completely reversed by NO precursor L-arginine stereoselectively as D-arginine failed to reverse the suppressed IAS relaxation. Sodium nitroprusside caused a decrease in IASP that was modified neither by the neurotoxin tetrodotoxin nor by L-NNA. Furthermore, the decrease in IASP by the direct-acting beta-adrenoceptor agonist isoproterenol was also not modified by the inhibitor of NO synthase. It is concluded that NO or an NO-like substance is an important mediator of IAS relaxation in response to noradrenergic, noncholinergic nerve stimulation.     

Colocalization of NADPH-diaphorase staining and VIP immunoreactivity in neurons in opossum internal anal sphincter

Nitric oxide and vasoactive intestinal polypeptide (VIP) are important inhibitory neurotransmitters mediating relaxation of the internal anal sphincter. The location and coexistence of these two neurotransmitters in the internal anal sphincter has not been examined. We performed a double-labeling study to examine the coexistence of nitric oxide synthase and VIP in the oppossum internal anal sphincter using the NADPH-diaphorase technique which is a histochemical stain for nitric oxide synthase. In perfusion-fixed, frozen-sectioned tissue, VIP-immunoreactive neurons were labeled using immunofluorescence histochemistry. After photographing the VIP-immunoreactive neurons, nitric oxide synthase was labeled using the NADPH-diaphorase technique. Ganglia containing neuronal cell bodies were present in the myenteric plexus for the entire extent of the internal anal sphincter. VIP-immunoreactive and NADPH-diaphorase-positive neurons were present in ganglia in the myenteric as well as the submucosal plexuses. Most of the VIP-immunoreactive neurons were also NADPH-diaphorase positive. VIP and nitric oxide synthase are present and frequently coexist in neurons in the internal anal sphincter of the opossum. These neurons may be an important source of inhibitory innervation mediating the rectoanal reflex-induced relaxation of the sphincter. The demonstration of the coexistence of these two neurotransmitters will be of fundamental importance in unraveling their relationship and interaction in the internal anal sphincter as well as other systems.Supported by DK-02094 (RBL) and DK-35385 (SR) from the National Institutes of Health and an institutional grant from Thomas Jefferson University.     

Histopathology of the internal anal sphincter in chronic anal fissure

A prospective study of 18 consecutive patients undergoing unilateral, partial-thickness, distal, internal sphincterotomy for the treatment of chronic anal fissure was performed. Biopsies were taken from the base of the fissure and from the lateral muscle before division. Normal specimens were taken from the internal anal sphincter of patients undergoing abdominoperineal resection. Specimens confirmed the presence of fibrosis throughout the internal anal sphincter in patients with anal fissures, but none in controls.     

Pathophysiologic role of the internal anal sphincter in chronic anal fissure

Internal anal sphincter manometric and myoelectrical investigations were performed under basal conditions and in response to rectal distension in 17 patients with chronic anal fissures and 15 controls. Measurement of sphincter pressures were carried out by pull-through technique, using water perfused open-tip-catheters. Electrical signals were obtained employing concentric needle electrodes inserted into the internal anal sphincter. No statistically different resting pressures were noted between patients with fissures and controls. Just so no significant difference were found in frequency and amplitude of slow potentials generated by the internal and sphincter. Neither amplitude or frequency correlate with anal sphincter pressures. In both groups, transient rectal distension produced relaxation of the internal sphincter and were associated with inhibition or irregularity of electric activity. Distribution and amplitude of internal overshoot contraction showed no difference in both groups. It can be concluded that internal sphincter spasm can not be considered as the sole cause for persistence of fissures.     

Endosonographic variations in the normal internal anal sphincter

Anal endosonography provides clear images of the internal anal sphincter. Forty-two controls have been studied to establish a range for thickness and echogenicity of the normal internal sphincter, and any physical correlate for these observations. No relationship was found between the thickness of the internal anal sphincter and body weight, height or gender, but there was a significant correlation for thickness with age (p<0.001), the 95% confidence interval being 2.4–2.7 mm <55 years and 2.8–3.4 mm >55 years. Hyperechogenicity of the internal sphincter was significantly associated with an age >55 years (P<0.01) and a thickness >2.8 mm (p<0.05). This has not been observed previously and suggests a histological change in the sphincter as it ages.

---

Résumé L'endosonographie anale fournit des images claires du sphincter anal. 42 contrôles ont été étudiés pour établir les variations d'épaisseur et d'échogénicité du sphincter anal interne normal ainsi que toute corrélation avec l'aspect physique du malade. Aucune relation n'a été trouvée entre l'épaisseur du sphincter anal interne et le pois corporel, la hauteur ou le sexe. Par contre, il y avait une corrélation significative de l'épaisseur avec l'âge (p<0,001), l'intervalle de confiance à 95% étant de 2,4–2,7 mm au-dessous de 55 ans et de 2,7–3,4 mm au-dessus de 55 ans. Une hyperéchogénicité du sphincter interne était associée de façon significative avec un âge supérieur à 55 ans (p<0,01) et une épaisseur supérieure à 2,8 mm (p<0,05). Ceci n'avait pas été observé auparavant et suggère des modifications histologiques du sphincter avec l'âge.

     

Influence of Parks' anal retractor on anal sphincter pressures

PURPOSE: The effects of the Parks' anal retractor on anal sphincter function were studied in a prospective, randomized trial. A closed hemorrhoidectomy was performed intraanally in 20 patients using the Parks' anal retractor; in 20 other patients, the procedure was done perineally without the use of a retractor. METHODS: Anal manometry was performed before and at 6 and 12 weeks after hemorrhoidectomy. RESULTS: Mean squeeze pressure decreased by 4 percent whether or not a retractor was used. Mean resting pressure decreased by 23 percent after use of Parks' anal retractor (P=0.01) compared with 8 percent when it was not used (P >0,05). CONCLUSIONS: The internal anal sphincter is easily damaged with the use of the Parks' anal retractor. When possible, its use should be avoided to obtain better manometric and functional results.No reprints are available.     

Relaxation of the internal anal sphincter in anorectal surgery

Summary and Conclusions Fourteen hundred consecutive cases of local anesthesia in anorectal surgery were reviewed. There was one superflcial abscess of doubtful etiology which occurred two weeks postoperatively and which was cured by incision and drainage. There were no other complications or side effects except transient hypertension in 20 per cent of the cases and these responded immediately to inhalation of amyl nitrite. The average hospital stay postoperatively was four days. Relaxation and hemostasis was adequate in every instance.     

Clinical outcome of anterior overlapping external anal sphincter repair with internal anal sphincter imbrication

Fecal incontinence caused by overt anterior sphincter defects sustained during childbirth is usually treated by a delayed overlapping repair of the external anal sphincter. However, an obstetric trauma is frequently associated with disruption of the perineal body and loss of the distal rectovaginal septum. Data regarding a combined repair, consisting of restoration of the rectovaginal septum and perineal body, overlapping external anal sphincter repair, and imbrication of the internal anal sphincter, are scanty. PURPOSE: This prospective study was aimed at the following: 1) evaluating the clinical outcome of such an anterior anal repair in patients with fecal incontinence caused by obstetric trauma; 2) comparing the functional results with those obtained in a historical group of patients who underwent a conventional direct sphincter repair. METHODS: During the period between 1973 and 1989, 24 female patients (median age, 44 (range, 28–67) years) with fecal incontinence underwent direct sphincter repair (Group I). During the period between 1989 and 1994, a consecutive series of 31 female patients (median age, 46 (range, 23–78) years) with fecal incontinence underwent anterior anal repair (Group II). RESULTS: At two years of follow-up, continence had been restored in 15 patients (63 percent) in Group I, whereas restoration of continence was successful in 21 patients (68 percent) in Group II. CONCLUSION: The more complex anterior anal repair fails to confer clinical benefit compared with the rather simple direct sphincter repair.Read at the meeting of The American Society of Colon and Rectal Surgeons, Montreal, Quebec, Canada, May 7 to 12, 1995.     

The internal anal sphincter can not close the anal canal completely

We determined the maximum closing capability of the internal anal sphincter muscle ring in vitro and in vivo. The internal sphincter, 4 to 6 mm thick, cannot close the anal canal hermetically, not even during maximal contraction. The blood-filled anal cushions have to till up an intrasphincteric gap of at least 7 to 8 mm in diameter.

---

Résumé Nous avons déterminé la capacité maximale de fermeture du sphincter anal interne in vitro et in vivo. Le sphincter interne (4 à 6 mm d'épaisseur) ne peut occlure hermétiquement le canal anal même durant la contraction anale maximale. Les coussinets anaux remplis de sang ont a remplir un vide intra-sphinctérique d'au moins 7 à 8 mm de diamètre.

     

Effect of lateral sphincterotomy on internal anal sphincter function

PURPOSE: This study was designed to investigate the effect of lateral sphincterotomy on internal anal sphincter function in patients with chronic anal fssure. METHODS: Using an eight-channel perfusion catheter and computerized data analysis, a prospective manometric study was performed on patients with chronic anal fissure undergoing lateral sphincterotomy (LS). RESULTS: Mean resting pressure (MRP) in patients with anal fissure (85.1 mmHg) was significantly higher (P=0.012) than control subjects (63.3 mmHg). One week following LS there was a significant reduction in MRP (50.0 mmHg;P=0.0014), and this was maintained when reassessed five weeks later (MRP=56.4 mmHg;P=0.0019). There was no significant difference in coefficent of variation (a measure of the degree of manometric asymmetry of the anal canal) in the control group (mean, 8.9 percent) and in patients with anal fissure (mean, 7.7 percent;P=0.43). LS created a significant increase in anal canal resting manometric asymmetry when assessed at one (mean, 17.3 percent;P=0.0013) and six weeks (mean, 11.7 percent;P=0.027) after the procedure. CONCLUSION: LS produces a global and symmetric decrease in anal canal resting pressure. In addition, it produces a significant increase in manometric asymmetry of the resting anal canal by creating a detectable segmental defect.Read at the Tripartite Meeting of the Soceity of University Surgeons, Jackson, Mississippi, February 8 to 12, 1994.     

Neuropeptides in the internal anal sphincter in neurogenic faecal incontinence

The internal anal sphincter has both an intrinsic and extrinsic innervation which modulates its activity. While the nature of the extrinsic innervation has been well characterised, the same is not true of the intrinsic innervation. Although a variety of neurotransmitters have been identified in the human internal anal sphincter, their physiological role in health, and possible involvement in disease processes, have received little attention. Using immunohistochemistry we have studied the distribution and nerve fibre densities of a range of neuropeptides in the internal anal sphincter from 12 cancer patients (controls) and from 16 patients with neurogenic faecal incontinence. We have also studied the in vitro effect of vasoactive intestinal peptide, neuropeptide tyrosine, and galanin on isolated preparations of the internal anal sphincter from 11 cancer controls and 5 patients with neurogenic faecal incontinence. There was no difference in either the distribution or density of the neuropeptides between the 2 groups of patients, and there was no qualitative difference in the in vitro responses of the sphincter to the neuropeptides. These findings suggest that these neuropeptide components of the intrinsic innervation of the internal anal sphincter are unaffected in patients with neurogenic faecal incontinence.

---

Résumé Le sphincter anal interne a une innervation intrinsèque et extrinsèque qui règle son activité. Tandis que la nature de l'innervation extrinséque a été bien caractérisée il n'en est pas de même pour l'innervation intrinséque. Quoiqu'une variété de neurotransmetteurs a été identifiée dans le sphincter anal interne humain, le rôle physiologique chez l'adulte sain et leur possible participation dans les processus pathologiques ont été peu étudiés. Par immunohistochimie, nous avons étudié la distribution et la densité dans les fibres nerveuses d'une série de neuropeptides au niveau du sphincter anal interne de 12 patients atteints de cancer (contrôle) et de 16 patients avec une incontinence fécale neurogénique. Nous avons aussi étudié l'effet in vitro du VIP, neuropeptide tyrosine, et galanine sur des préparations isolées de sphincter anal interne de 11 cancers contrôles et de 5 patients avec incontinence neurogénique. Il n'y avait pas de différence dans la distribution ou la densité des neuropeptides entre les deux groupes de patients et il n'y avait pas de différence qualitative dans les réponses in vitro du sphincter aux neuropeptides. Ces résultats suggèrent que ces neuropeptides composant de l'innervation intrinséque du sphincter anal interne ne sont pas affectés chez les patients avec incontinence neurogénique.

     

Nitric oxide deficiency in the internal anal sphincter of patients with chronic anal fissure

Anal fissure is a common condition affecting young to middle-aged adults. It causes severe pain on defecation and rectal bleeding. The aetiology remains uncertain. Spasm of the internal anal sphincter is a constant feature. Nitric oxide (NO) is the major inhibitory neurotransmitter of the internal anal sphincter (IAS). In other spasmodic conditions of the GI tract a lack of normal nitric oxide synthase (NOS) activity has been reported. The aim of this preliminary study was to compare the presence of NOS in the internal sphincters of patients with and without chronic anal fissure. Internal anal sphincter biopsies were taken under general anaesthesia from patients having lateral internal sphincterotomy for chronic anal fissure and from sphincter of patients having abdominoperineal resections as controls. Sections of IAS were stained to show the presence of NADPH diaphorase (and hence presence of NOS). Internal anal sphincter was taken from 6 patients with chronic anal fissure and 6 controls. IAS taken from patients with chronic anal fissure showed little NOS presence compared with controls. It may be that there is an abnormal failure of relaxation of internal sphincter in those patients who develop chronic anal fissure caused by an intrinsic lack of neural NOS in the internal anal sphincter.     

The role of internal sphincter in chronic anal fissures

Changes in anal sphincteric manometric pressures in response to rectal distention were measured in eight patients with chronic anal fissures and were compared with the of ten controls. No statistically different resting pressures were noted between the two groups. Overshoot phenomenon was more commonly seen in patients with fissure. There were no differences in the anal sphincteric pressures after lateral internal sphincterotomy (LIS) or fissurectomy midline sphincterotomy (FMS). All fissures healed postoperatively, irrespective of the surgical technique (LIS or FMS) or the pressure readings. It can be concluded that the therapeutic effect of sphincterotomies might at least in part be due to anatomic widening of the anal canal rather than to decreased resting pressures of the internal sphincter. This study was supported by a grant from the American Society of Colon and Rectal Surgeons Research Foundation and was presented as part of a symposium at the annual meeting of the American Society of Colon and Rectal Surgeons, Colorado Springs, Colorado, June 7 to 11, 1981.     

The effect of loperamide on bowel habits and anal sphincter function in patients with ileoanal anastomosis

The effect of loperamide on stool frequency, volume, and weight and on the function of the internal (IAS) and the external (EAS) anal sphincter was investigated in 19 patients with straight ileoanal anastomosis. Nine patients had intact anal sphincter function (group I), and in the other 10 the function of the anal sphincters was impaired (group II). After 72 h without any medication, the patients were investigated on a standard diet on 2 consecutive days: the 1st day with placebo, and the 2nd day with loperamide (16 mg). Stool collection and anal sphincter manometry/electromyography (EMG) were done on both days. The median number of stools was reduced from 10 and 13.5 to 6 and 7 per 24 h (p less than 0.01), and the fecal weight reduced from 600 and 900 g to 400 and 500 g (p less than 0.01) from the placebo day to the loperamide day in groups I and II, respectively. The tone of the IAS was significantly increased by loperamide in group I but remained unchanged in group II patients. The EAS function, determined by EMG and pressure measurements, was not significantly changed in any group by loperamide.     

Neuromyogenic properties of the internal anal sphincter: therapeutic rationale for anal fissures

Lateral sphincterotomy diminishes internal anal sphincter hypertonia and thereby reduces anal canal pressure. This improves anal mucosal blood flow and promotes the healing of anal fissures. However, sphincterotomy can be associated with long term disturbances of sphincter function. The optimal treatment for an anal fissure is to induce a temporary reduction of anal canal resting pressure to allow healing of the fissure without permanently disrupting normal sphincter function. Broader understanding of the intrinsic mechanisms controlling smooth muscle contraction has allowed pharmacological manipulation of anal sphincter tone. We performed an initial Medline literature search to identify all articles concerning "internal anal sphincter" and "anal fissures". This review is based on these articles and on additional publications obtained by manual cross referencing. Internal anal smooth muscle relaxation can be inhibited by stimulation of non-adrenergic non-cholinergic enteric neurones, parasympathetic muscarinic receptors, or sympathetic beta adrenoceptors, and by inhibition of calcium entry into the cell. Sphincter contraction depends on an increase in cytoplasmic calcium and is enhanced by sympathetic adrenergic stimulation. Currently, the most commonly used pharmacological agent in the treatment of anal fissures is topical glyceryl trinitrate, a nitric oxide donor. Alternative agents that exhibit a similar effect via membrane Ca2+ channels, muscarinic receptors, and alpha or beta adrenoceptors are also likely to have a therapeutic potential in treating anal fissures.